chr8-89953351-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_002485.5(NBN):c.1738G>A(p.Val580Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V580G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.05

Publications

1 publications found

Variant links:

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

NBN Gene-Disease associations (from GenCC):

Nijmegen breakage syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
idiopathic aplastic anemia
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13184163).

BP6

Variant 8-89953351-C-T is Benign according to our data. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187. Variant chr8-89953351-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 239187.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.1738G>A	p.Val580Ile	missense_variant	Exon 11 of 16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.1738G>A	p.Val580Ile	missense_variant	Exon 11 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461292

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111792

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Uncertain:2

Mar 24, 2021

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 580 of the NBN protein (p.Val580Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 239187). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Benign:1

Feb 06, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.

Eigen

Benign

-0.0025

Eigen_PC

Benign

-0.022

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

1.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.48

N;N;.

REVEL

Benign

0.073

Sift

Benign

0.17

T;T;.

Sift4G

Benign

0.19

T;T;D

Polyphen

0.99

D;.;.

Vest4

0.092

MutPred

0.35

Loss of helix (P = 0.0093);.;.;

MVP

0.78

MPC

0.082

ClinPred

0.44

GERP RS

4.4

PromoterAI

0.0041

Neutral

(source)

Varity_R

0.060

gMVP

0.059

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over